Although childhood-onset Systemic Lupus Erythematosus (cSLE) has similar disease manifestations as SLE in adults, children often have more severe multi-organ involvement, and up to 80% of them have kidney involvement, i.e. lupus nephritis (LN). The International Societies for Nephrology & Renal Pathology (ISN/RPS) Classification of LN was developed to improve predictive validity of kidney histology with focus on adults with SLE. The ISN/RPS Classification reports on histological features of LN severity, inflammatory activity and irreversible LN -damage. Despite remaining the gold standard for diagnosing LN, kidney biopsies are impractical to assess the course of LN given their invasiveness and cost. Indeed, there is an important gap in the scientific knowledge of how to discriminate LN activity that is amenable to antiinflammatory therapy from irreversible fibrotic and sclerotic kidney damage that is not. The objective of this application is to make accurate validated measures of LN activity and damage for cSLE available to clinicians and researchers. The central hypotheses to be tested are 1) that current LN measures have insufficient sensitivity and specificity to effectively assess the course of LN and that 2) LN indices which include novel renal biomarkers (RBM), i.e. neutrophil gelatinase associated lipocalin, transferrin, ceruloplasmin, al-acid glycoprotein, chemokine ligand 2, adiponectin, hepcidin, liver-type fatty acid binding protein, and lipocalin-like prostaglandin-D synthetase, can noninvasively and accurately assess LN activity and damage with cSLE. We will use banked samples, longitudinal clinical data from 154 patients participating in the CARRA Lupus Registry and enroll 50 additional cSLE patients at the time of kidney biopsy to test the central hypotheses and achieve the objectives of this application by pursuing the following specific aims: Aim #1a: To assess the construct and discriminant validity of current measures of LN activity in cSLE. Aim #1b: To develop and initially validate for Children a Renal Activity Index (C-RAI) to non-invasively monitor LN activity. Aim #2: To develop and initially validate for Children a Lupus Nephritis Index for Damage (C-LID). Our expectations are that this study will provide a thorough validation of current LN indices, confirming their suboptimal ability to reflect the LN activity & damage. We anticipate developing more accurate LN indices, i.e. the C-RAI and the C-LID, and carry out initial validation procedures. The C-RAI and C-LID will facilitate RELEVANCE (See instructions): End-stage renal disease (ESRD) is the sequelae of LN that is diagnosed too late and managed inadequately due to insufficient clinical tools to monitor Its course. Our research is poised to have a maior impact on the U.S. public health, because LN constitutes the 3rd most common cause of ESRD and its therapy costs $240 million annually. High-quality clinical indices will increase the accuracy by which clinicians can diagnose LN activity and predict its course, enabling them to implement appropriate therapeutic regimens eady. This will likely help reduce kidney damage, diminish the frequency of ESRD, and lower the cost of renal replacement therapy.